Pyrazol-5-ones

ABSTRACT

1-Substituted pyrazole-5-ones of the formula ##STR1## and pharmaceutically acceptable, nontoxic salts thereof, wherein R is hydrogen or amino; 
     R 1  is hydrogen, alkyl, alkenyl, unsubstituted or substituted aryl or unsubstituted or substituted aralky; 
     X is 
     A. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, ethylene wherein 1 hydrogen atom on each of the two carbon atoms is substituted by alkyl of 1 to 4 carbon atoms or said ethylene which is linked to R 2  via an oxygen or sulphur atom; 
     B. propenyl, propenyl wherein 1 hydrogen atom on one, two or three of the carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, said propenyl being linked to the N 1  atom of the pyrazol ring via its methylene moiety; or 
     C. methylene; 
     Provided that when X is methylene, R 1  is not hydrogen if R is amino; 
     R 2  is aryl unsubstituted or substituted by: 
     A. 1 or 2 of the same or different substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and lower alkoxy; 
     B. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms; 
     C. alkylamino, dialkylamino, cyano, trifluoromethoxy, nitro, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, or said carbamoyl wherein the nitrogen atom is a member of a heterocyclic ring, sulphamyl, alkylsulphamyl, dialkylsulphamyl, or said sulphamyl wherein the nitrogen is a member of a heterocyclic ring, or --SO n  alkyl wherein n is 0, 1 or 2; 
     D. alkylamino, dialkylamino, cyano, trifluoromethoxy, nitro, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, or said carbamoyl wherein the nitrogen atom is a member of a heterocyclic ring, sulphamyl, alkylsulphamyl, dialkylsulphamyl or said sulphamyl wherein the nitrogen is a member of a heterocyclic ring, or --SO n  -- alkyl wherein n is 0, 1 or 2, and 1 or 2 of the same or different substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, and trifluoromethyl; or 
     E. a fused, saturated or unsaturated 5-, 6-, or 7-membered ring or said ring containing 1 or 2 oxygen or sulphur atoms; 
     are useful for their diuretic, saluretic, antihypertensive and antithrombotic effects.

CROSS REFERENCE

This is a division of Ser. No. 461,285 filed Apr. 15, 1974, now U.S.Pat. No. 3,952,008.

the present invention relates to 1-substituted pyrazol-5-ones, processesfor their production, pharmaceutical compositions useful for effectingdiuresis, saluresis and for treating hypertension and thromboses inhumans and animals wherein said 1-substituted pyrazol-5-ones are theactive agent, and to methods of effecting diuresis and saluresis inhumans and animals and methods of treating hypertension and thrombosesin humans and animals which comprises administering said compounds tosuch humans or animals.

3-Aminopyrazoles have already been used as color-coupling agents forcolor photography (A. Weissberger et al., J. Amer. Chem. Soc., 64, 2183(1942)) and intermediate products for the preparation of color-couplingagents (British Pat. No. 599,919; U.S. Pat. No. 2,367,523; U.S. Pat. No.2,376,380; U.S. Pat. No. 2,511,231; U.S. Pat. No. 2,600,788; U.S. Pat.No. 2,619,419; U.S. Pat. No. 2,672,417).

Certain pyrazol-5-one derivatives are also used as antipyretics,analgesics and antiphlogistics (compare G. Ehrhart and H. Ruschig,Arnzneimittel (Medicines), Volume 1, page 148 (1972)).

We have now discovered a new group of 1-substituted pyrazol-5-ones whichhave strong diuretic, saluretic, antihypertensive and antithromboticproperties.

More particularly, the present invention is concerned with 1-substitutedpyrazol-5-ones of the formula ##STR2## or a pharmaceutically acceptable,nontoxic salt thereof wherein R is hydrogen or amino;

R¹ is hydrogen, alkyl, preferably lower alkyl, alkenyl, preferably loweralkenyl, aryl, preferably monoaryl, unsubstituted or substituted bylower alkoxy, or aralkyl, preferably wherein the aryl moiety is amonoaryl moiety and the alkyl moiety is a lower alkyl moiety, saidaralkyl being either unsubstituted or substituted by lower alkoxy;

X is

a. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atomsis substituted by alkyl of 1 to 4 carbon atoms, ethylene wherein 1hydrogen atom on each of the two carbon atoms is substituted by alkyl of1 to 4 carbon atoms or said ethylene which is linked to R² via an oxygenor sulphur atom;

b. propenyl, propenyl wherein 1 hydrogen atom on one, two or three ofthe carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, saidpropenyl being linked to the N¹ atom of the pyrazol ring via itsmethylene moiety; or

c. methylene;

provided that when X is methylene, R¹ is not hydrogen if R is amino;

R² is aryl preferably aryl of 6 to 10 carbon atoms, unsubstituted orsubstituted by

a. 1 or 2 of the same or different substituents selected from the groupconsisting of halogen, trifluoromethyl, alkyl of 1 to 8 carbon atoms,alkenyl or 2 to 8 carbon atoms and lower alkoxy;

b. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7carbon atoms;

c. alkylamino, preferably lower alkylamino, dialkylamino, preferablydi(lower alkyl)amino, cyano, trifluoromethoxy, nitro, carbamoyl,alkylcarbamoyl, preferably lower alkylcarbamoyl, dialkylcarbamoyl, orsaid carbamoyl wherein the nitrogen atom is a member of a heterocyclicring, sulphamyl, alkylsulphamyl, preferably lower alkylsulphamyl,dialkylsulphamyl, preferably di(lower alkyl) sulphamyl, or saidsulphamyl wherein the nitrogen is a member of a heterocyclic ring, or--SO_(n) alkyl, preferably lower alkyl, wherein n is 0, 1 or 2;

d. alkylamino, preferably lower alkylamino, dialkylamino, preferablydi(lower alkyl)amino, cyano, trifluoromethoxy, nitro, carbamoyl,alkylcarbamoyl, preferably lower alkylcarbamoyl, dialkylcarbamoyl,preferably di(lower alkyl)carbamoyl, or said carbamoyl wherein thenitrogen atom is a member of a heterocyclic ring, sulphamyl,alkylsulphamyl, preferably lower alkylsulphamyl, dialkylsulphamyl,preferably di(lower alkyl)sulphamyl, or said sulphamyl wherein thenitrogen is a member of a heterocyclic ring, or --SO_(n) alkyl,preferably lower alkyl, wherein n is 0, 1 or 2, and 1 or 2 of the sameor different substituents selected from the group consisting of alkyl,preferably lower alkyl, alkenyl, preferably lower alkenyl, alkoxy,preferably lower alkoxy, halogen, and trifluoromethyl; or

e. a fused, saturated or unsaturated 5-, 6-, or 7-membered ring or saidring containing 1 or 2 oxygen or sulphur atoms;

As used hereinafter, the phrase, "compounds of the present invention ",includes both the pyrazol-5-ones and their pharmaceutically acceptable,nontoxic salts.

If X in formula I contains an asymmetric carbon atom, then the compoundsof the present invention may be isomers as well as racemates. Thecompounds of the present invention thus include all the optical isomers,as well as the racemates thereof.

In addition to the structure which is represented by formula I above,the compounds of the present invention may also be in one of thefollowing tautomeric forms or in the form of a mixture of suchtautomers: ##STR3## In addition, the 3-amino-pyrazol-5-ones according tothe present invention may also be present in the following imino forms:##STR4##

In formulas II, III, IV and V, R, R¹, R² are as above defined.

The compounds of the present invention may be produced according to thefollowing processes: A) A hydrazine of the formula

    R.sup.2 --X--NH--NH.sub.2                                  VI

wherein

R² and X are as above defined is reacted with an acetic acid derivativeof the formula ##STR5## wherein R¹ is as above defined,

Y is hydroxy, alkoxy, preferably lower alkoxy, aralkoxy, preferablymonoaryl lower alkoxy, amino, or alkylamino, preferably loweralkylamino; and either

Y' is hydrogen and

Y" is cyano, or --CH=O, or

Y' and Y" together form the moiety ##STR6## wherein Y'" is alkoxy,preferably lower alkoxy, aryloxy, preferably monoaryloxy, alkylmercapto,preferably lower alkylmercapto, aralkylmecapto, preferablymonoaryl(lower alkyl)mercapto, or amino; either in the presence or theabsence of an inert solvent and either in the presence or the absence ofa basic or acidic catalyst such as an alkaline metal hydroxide,carbonate, or alkaline earth metal hydroxide or carbonate, or hydrogenhalide acids, sulphuric acid or sulphonic acids at a temperature of fromabout 10° to about 200° C;

B. reacting a compound of the formula:

    R.sup.2 --X--A                                             VIII

wherein

R² and X are as above defined and

A is a moiety capable of being cleaved during the course of thereaction, preferably halogen, dialkyloxonium, preferably di(loweralkyl)oxonium, dialkylsulphonium, preferably di(lower alkyl) sulphonium,trialkylammonium, preferably tri(lower alkyl)ammonium, arylsulphonicacid, preferably monoarylsulphonic acid, or trifluoromethylsulphonicacid,

with a pyrazol-5-one of the formula ##STR7## wherein R and R¹ are asabove defined, either in the presence or the absence of an inertsolvent, and either in the present or the absence of an inorganic ororganic base such as an alkali metal hydroxide, carbonate, alcoholate,hydride or amide, at a temperature of from about 10° to about 200° C;

C. when R is amino, reacting a pyrazol-5-one of the formula ##STR8##wherein R¹, R² and X are as above defined, and

Z is halogen, alkoxy, preferably lower alkoxy, aralkoxy, preferablymonoaryl(lower alkoxy), alkylmercapto, preferably (lower alkyl)mercapto,or aralkylmercapto, preferably monoaryl(lower alkyl)mercapto,

with ammonia, either in the presence or the absence of an inert solventat a temperature of from about 20° to about 220° C, preferably fromabout 50° to about 150° C, either under atmospheric pressure or underelevated pressure;

D. when R is amino, reacting a pyrazol-5-one of the formula ##STR9##wherein R¹, R² and X are as above defined, and

Z¹ is alkyl, preferably lower alkyl, aryl, preferably monoaryl, oraralkyl, preferably monoaryl(lower alkyl),

under hydrolization conditions with an acid or base either in thepresence or the absence of an inert solvent at a temperature of fromabout 20° to about 200° C; or

E) when R¹ is hydrogen reacting an acetylenecarboxylic acid of theformula ##STR10## wherein Z² is hydroxy, alkoxy, preferably lower loweralkoxy, aralkoxy, preferably monoaryl(lower alkoxy), amino oralkylamino, preferably (lower alkyl)amino,

with a hydrazine of the formula

    R.sup.2 --X--NH--NH.sub.2                                  VI

wherein

R² is as above defined either in the presence or the absence of an inertsolvent at a temperature of from about 50° to about 200° C.

The five processes A to E above set forth are hereinafter referred to asProcess Variants A to E.

The optical isomers or enantiomers of the compounds according to thepresent invention can be separately prepared according to methods knownfrom the literature (compare, for example, Houben Weyl, Methoden derorganischen Chemie, IV/2, pages 509 et seq.) by interaction of theracemic forms of the compounds of the invention with a chiral medium,preferably by reaction of the racemate with the derivative of anoptically active acid (for example, camphorsulphonic acid,bromocamphorsulphonic acid or quinic acid) or an optically active base(for example, brucine, morphone or strychnine). A mixture ofdiastereomeric reaction products is thus obtained which can be separatedand prepared in a pure form with the aid of physico-chemical methodssuch as, for example, fractionation, and can subsequently be resolvedinto optically pure components.

Alternatively, the compound of the present invention can be prepared inoptically active form by producing them by one of the methods describedabove using optically active precursors. Thus:

a. an optically pure hydrazine of the formula VI (which can be preparedby known methods) can be reacted with an acetic acid derivative of theformula VII according to Process Variant A; or

b. an optically pure pyrazol-5-one derivative of the formula X (whichcan be obtained by known methods) can be reacted with ammonia; or

c. an optically pure pyrazol-5-one of the formula XI can be hydrolyzed;or

d. an optically pure hydrazine of the formula VI can be reacted with anacetylene-carboxylic acid derivative of the formula XII.

The pyrazol-5-ones of formula I and their pharmaceutically acceptable,nontoxic salts can be interconverted according to manners per se knownin the art.

Surprisingly, the new compounds of the invention display strongdiuretic, saluretic, antithrombotic and antihypertensive actions.Hitherto, diuretic, saluretic, antithrombotic and antihypertensiveactions have not been disclosed for the related pyrazol-5-onederivatives known from the prior art, so that the compounds according tothe present invention both represent a novel class of compounds and inrespect of these specific pharmaceutical actions can be regarded as anenrichment of pharmacy.

Depending on the nature of the starting compounds used, the synthesis ofthe compounds of the invention can be represented by the followingillustrative equations, wherein3-amino-4-methyl-1-(β-phenylmercapto-ethyl)-pyrazol-5-one,4-methyl-1-(4-chlorobenzyl)-pyrazol-5-one,4-methyl-1-(β-(3-chlorophenyl)-ethyl)-pyrazol-5-one,3-amino-1-(β-phenylethyl)-pyrazol-5-one,3-amino-1-(β-(3-chlorophenyl)-ethyl)pyrazol-5-one and1-(4-chlorobenzyl)-pyrazol-5-one have been chosen as examples and thepossible intermediate stages of the reaction sequence, products of whichcan sometimes be isolated, have not been shown. ##STR11##

According to one embodiment of the present invention

R is hydrogen or amino;

R¹ is hydrogen, lower alkyl, lower alkenyl, monoaryl unsubstituted orsubstituted by lower alkoxy or aralkyl wherein the aryl moiety is amonoaryl moiety and the alkyl moiety is a lower alkyl moiety, saidaralkyl being unsubstituted or substituted by lower alkoxy;

R² is aryl of 6 to 10 carbon atoms unsubstituted or substituted by:

a. 1 or 2 of the same or different substituents selected from the groupconsisting of halogen, trifluromethyl, alkyl of 1 to 8 carbon atoms,alkenyl of 2 to 8 carbon atoms and lower alkoxy;

b. monoalkylamino of 1 to 4 carbon atoms in the alkyl moiety,dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, cyano,trifluoromethoxy, nitro, alkylcarbamoyl of 1 to 4 carbon atoms in thealkyl moiety, di(lower alkyl)carbamoyl of 1 to 4 carbon atoms in eachalkyl moiety, or said carbamoyl wherein the nitrogen atom is a member ofa heterocyclic ring, sulphamyl, alkylsulphamyl of 1 to 4 carbon atoms inthe alkyl moiety, dialkylsulphamyl of 1 to 4 carbon atoms in each alkylmoiety or said sulphamyl wherein the nitrogen atom is a member of aheterocyclic ring, or--SO_(n) alkyl wherein n is 0, 1 or 2 and and thealkyl moiety has 1 to 4 carbon atoms;

c. monoalkylamino of 1 to 4 carbon atoms in the alkyl moiety,dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, cyano,trifluoromethoxy, nitro, alkylcarbamoyl of 1 to 4 carbon atoms in thealkyl moiety, di(lower alkyl)carbamoyl of 1 to 4 carbon atoms in eachalkyl moiety or said carbamoyl wherein the nitrogen atom is a member ofa heterocyclic ring, sulphamyl, alkylsulphamyl of 1 to 4 carbon atoms inthe alkyl moiety, dialkylsulphamyl of 1 to 4 carbon atoms in each alkylmoiety or said sulphamyl wherein the nitrogen atom is a member of aheterocyclic ring, or --SO_(n) alkyl wherein n is 0, 1 or 2 and thealkyl moiety has 1 to 4 carbon atoms, and 1 or 2 of the same ordifferent substituents selected from the group consisting of loweralkyl, lower alkenyl, lower alkoxy, halogen and trifluoromethyl; or

d. a fused, saturated or unsaturated 5-, 6-, 7-membered ring or saidring containing 1 or 2 oxygen or sulphur atoms.

According to another embodiment of the present invention

R¹ is hydrogen, lower alkyl, lower alkenyl, phenyl unsubstituted orsubstituted by lower alkoxy or benzyl unsubstituted or substituted bylower alkoxy; and

R² is aryl of 6 to 10 carbon atoms unsubstituted or substituted by:

a. 1 or 2 of the same or different substituents selected from the groupconsisting of halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms,alkenyl of 2 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms;

b. monoalkylamino of 1 to 4 carbon atoms in the alkyl moiety,dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, cyano,trifluoromethoxy, nitro, alkylcarbamoyl of 1 to 4 carbon atoms in thealkyl moiety, di(lower alkyl)carbamoyl of 1 to 4 carbon atoms in eachalkyl moiety, or said carbamoyl wherein the nitrogen atom is a member ofa heterocyclic ring, sulphamyl, alkylsulphamyl of 1 to 4 carbon atoms inthe alkyl moiety, dialkylsulphamyl of 1 to 4 carbon atoms in each alkylmoiety, or said sulphamyl wherein the nitrogen atom is a member of aheterocyclic ring, or --SO_(n) alkyl wherein n is 0, 1 or 2 and and thealkyl moiety has 1 to 4 carbon atoms;

c. monoalkylamino of 1 to 4 carbon atoms in the alkyl moiety,dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, cyano,trifluoromethoxy, nitro, alkylcarbamoyl of 1 to 4 carbon atoms in thealkyl moiety, di(lower alkyl)carbamoyl of 1 to 4 carbon atoms in eachalkyl moiety, or said carbamoyl wherein the nitrogen atom in a member ofa heterocyclic ring, sulphamyl, alkylsulphamyl of 1 to 4 carbon atoms inthe alkyl moiety, dialkylsulphamyl of 1 to 4 carbon atoms in each alkylmoiety or said sulphamyl wherein the nitrogen atom is a member of aheterocyclic ring, or --SO_(n) alkyl wherein n is 0, 1 or 2 and thealkyl moiety has 1 to 4 carbon atoms, and 1 or 2 of the same ordifferent substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of 2 to 4carbon atoms, halogen and trifluoromethyl; or

d. a fused, saturated or unsaturated 5-, 6-, or 7 -membered ring or saidring containing 1 or 2 oxygen or sulphur atoms.

According to another embodiment of the present invention

R¹ is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbonatoms, phenyl unsubstituted or substituted by alkoxy of 1 to 4 carbonatoms or benzyl unsubstituted or substituted by alkoxy of 1 to 4 carbonatoms;

X is

a. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atomsis substituted by alkyl of 1 to 4 carbon atoms, ethylene wherein 1hydrogen atom on each of the two carbon atoms is substituted by alkyl of1 to 4 carbon atoms or said ethylene which is linked to R² via an oxygenor sulphur atom;

b. propenyl, propenyl wherein 1 hydrogen atom on one or two of thecarbon atoms is substituted by alkyl of 1 to 4 carbon atoms, saidpropenyl being linked to the N¹ atom of the pyrazol ring via itsmethylene moiety; or

c. methylene;

provided that when X is methylene, R¹ is not hydrogen if R is amino;

R² is phenyl; naphthyl; or phenyl substituted by:

a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 8 carbonatoms, or alkenyl moieties of 2 to 8 carbon atoms;

b. 1 or 2 alkoxy moieties of 1 to 6 carbon atoms;

c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7carbon atoms;

d. 1 or 2 halogens;

e. 1 or 2 trifluoromethyl moieties;

f. trifluoromethoxy, nitro or cyano;

g. dialkylamino of 1 to 4 carbon atoms in each alkyl moiety;

h. alkylcarbamoyl, dialkylcarbamoyl, sulphamyl or dialkylsulphamyl,wherein alkyl is of 1 to 4 carbon atoms;

i. --SO_(n) alkyl wherein n is 0 or 2 and alkyl is of 1 to 4 carbonatoms; or

j. a fused, saturated or unsaturated 5-, 6- or 7 -membered isocyclic orheterocyclic ring or said ring having 1 sulphur atom or 1 or 2 oxygenatoms as ring members.

According to another embodiment of the present invention

R¹ is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbonatoms, phenyl, benzyl, or phenyl or benzyl substituted by alkoxy of 1 or2 carbon atoms;

X is

a. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atomsis substituted by alkyl of 1 to 4 carbon atoms, ethylene wherein 1hydrogen atom on each of the two carbon atoms is substituted by alkyl of1 to 4 carbon atoms or said ethylene which is linked to R² via an oxygenor sulphur atom;

b. propenyl, propenyl wherein 1 hydrogen atom on one or two of thecarbon atoms is substituted by alkyl of 1 to 4 carbon atoms, saidpropenyl being linked to the N¹ atom of the pyrazol ring via itsmethylene moiety; or

c. methylene;

provided that when is methylene, R¹ is not hydrogen if R is amino;

R² is phenyl; naphthyl; or phenyl substituted by:

a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 4 carbonatoms or alkenyl moieties of 2 to 4 carbon atoms;

b. 1 or 2 alkoxy moieties of 1 to 4 carbon atoms;

c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl, of 5, 6 or 7carbon atoms;

d. 1 or 2 fluoro, chloro or bromo moieties;

e. 1 or 2 trifluoromethyl moieties;

f. trifluoromethoxy, nitro or cyano;

g. dialkylamino of 1 or 2 carbon atoms;

h. alkylcarbamoyl, dialkylcarbamoyl, sulphamyl or dialkylsulphamyl,wherein alkyl is of 1 to 4 carbon atoms;

i. --SO_(n) alkyl wherein n is 0 or 2 and alkyl is of 1 to 4 carbonatoms; or

j. a fused, saturated 5- or 6-membered ring.

According to another embodiment of the present invention

R¹ is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbonatoms, phenyl or benzyl;

X is

a. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atomsis substituted by alkyl of 1 to 4 carbon atoms, ethylene wherein 1hydrogen atom on each of the two carbon atoms is substituted by alkyl of1 to 4 carbon atoms or said ethylene which is linked to R² via an oxygenor sulphur atom;

b. propenyl, propenyl wherein 1 hydrogen atom on 1 of the carbon atomsis substituted by alkyl of 1 to 4 carbon atoms, said propenyl beinglinked to the N¹ atom of the pyrazol ring via its methylene moiety; or

c. methylene;

provided that when X is methylene, R¹ is not hydrogen if R is amino;

R² is phenyl; naphthyl; or phenyl substituted by:

a. 1 or 2 members selected from the group consisting of straight orbranched-chain alkyl and trifluoromethyl moieties of 1 to 4 carbonatoms;

b. alkoxy of 1 to 4 carbon atoms;

c. cycloalkyl of 5 or 6 carbon atoms;

d. 1 or 2 fluoro, chloro, bromo or iodo moieties;

e. chloro or bromo and alkyl of 1 or 2 carbon atoms, trifluoromethyl orsulphamyl;

f. trifluoromethoxy, nitro, cyclohexyl or dialkylamino of 1 or 2 carbonatoms;

g. carbamoyl or sulphamyl;

h. --SO_(n) alkyl wherein n is 0 or 2 and alkyl is of 1 to 4 carbonatoms; or

i. a fused, saturated, 5- or 6-membered ring.

According to another embodiment of the present invention

R¹ is hydrogen, methyl, ethyl, phenyl or benzyl;

X is

a. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atomsis substituted by alkyl of 1 or 2 carbons, ethylene wherein 1 hydrogenatom on each of the two carbon atoms is substituted by alkyl of 1 or 2carbon atoms, ethylene linked to R² via an oxygen atom or ethylenelinked to R² via a sulphur atom;

b. propenyl or propenyl wherein 1 hydrogen atom is substituted by alkylof 1 or 2 carbon atoms, said propenyl being linked to the N¹ atom of thepyrazol ring via its methylene moiety; or

c. methylene;

provided that when X is methylene, R¹ is not hydrogen if R is amino;

R² is phenyl; naphthyl; or phenyl substituted by fluorine, chlorine,bromine, iodine, trifluoromethyl, trifluoromethoxy, nitro, alkyl of 1 to4 carbon atoms, sulphamyl, dimethylamino, alkoxy of 1 to 4 carbon atoms,cyclohexyl, dichlorine, chlorine and methyl, chlorine and bromine,chlorine and fluorine, chlorine and sulphamyl, chlorine andtrifluoromethyl, dibromine, methyl and trifluoromethyl or by a fused,saturated, 5- or 6-membered ring.

According to another embodiment of the present invention

X is

a. ethylene, ethylene where 1 hydrogen on 1 carbon atom is substitutedby methyl or ethyl, ethylene wherein 1 hydrogen atom on each of the 2carbon atoms is substituted by methyl; or ethylene linked to R² via anoxygen or sulphur atom;

b. propenyl or propenyl wherein 1 hydrogen on 1 carbon atom issubstituted by methyl, said propenyl being linked to the N¹ atom of thepyrazole ring via its methylene moiety; or

c. methylene;

provided that when X is methylene, R¹ is not hydrogen if R is amino.

According to another embodiment of the present invention

R¹ is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl;

X is

a. ethylene, ethylene wherein 1 hydrogen atom of 1 carbon atom issubstituted by methyl and linked to R² via an oxygen or sulphur atom orethylene linked to R² via an oxygen or sulphur atom;

b. propenyl; or

c. methylene; provided that when X is methylene, R¹ is not hydrogen if Ris amino;

R² is phenyl naphthyl; or phenyl substituted by 1 or 2 chlorine, methyl,ethyl or trifluoromethyl moieties.

According to another embodiment of the present invention

R¹ is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl;

X is

a. ethylene, ethylene wherein 1 hydrogen atom of 1 carbon atom issubstituted by methyl and linked to R² via an oxygen or sulphur atom orethylene linked to R² via an oxygen or sulphur atom;

R² is naphthyl, phenyl or phenyl substituted by chlorine, methyl,trifluoromethyl, dichlorine, dimethyl, methyl and ethyl or methyl andtrifluoromethyl.

According to Process Variant A

Y is preferably hydroxy, alkoxy of 1 to 6 carbon atoms, especiallybranched alkoxy of 3 to 6 carbon atoms and especially of 1 or 2 carbonatoms, benzyloxy, amino, or alkylamino or dialkylamino of 1 to 4 andespecially 1 or 2 carbon atoms, and

Y' is hydrogen and

Y" is cyano, or --CH= O; or

Y' and Y" together form the moiety ##STR12## wherein Y'" is alkoxy of 1to 6 carbon atoms, benzyloxy, phenoxy, benzylmercapto or amino; and

R² is preferably phenyl; naphthyl; or phenyl substituted by:

a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 8 carbonatoms, or alkenyl moieties of 2 to 8 carbon atoms;

b. 1 or 2 alkoxy moieties of 1 to 6 carbon atoms;

c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7carbon atoms;

d. 1 or 2 halogens;

e. 1 or 2 trifluoromethyl moieties;

f. trifluoromethoxy, nitro or cyano;

g. dialkylamino of 1 to 4 carbon atoms in each alkyl moiety;

h. alkylcarbamoyl, dialkylcarbamoyl, sulphamyl or dialkylsulphamylwherein alkyl is of 1 to 4 carbon atoms;

i. --SO_(n) alkyl wherein n is 0 or 2 and alkyl is of 1 to 4 carbonatoms; or

j. a fused, saturated or unsaturated 5-, 6- or 7 -membered isocyclic orheterocyclic ring or said ring having 1 sulphur atom or 1 or 2 oxygenatoms as ring members.

The hydrazines of formula VI which are used as starting materialsaccording to Process Variant A are known in the literature or can beprepared by methods which are per se known. (Compare, for example,Houben-Weyl's Methoden der organischen Chemie (Methods of OrganicChemistry) Volume X, 2, page 6.)

Representative hydrazines of the formula VI include:

3-chlorobenzylhydrazine,

3-bromobenzylhydrazine,

4-chlorobenzylhydrazine,

4-bromobenzylhydrazine,

3,4-dichlorobenzylhydrazine,

3,4-dibromobenzylhydrazine,

4-chloro-3-bromobenzylhydrazine,

4-bromo-3-chlorobenzylhydrazine,

4-methylbenzylhydrazine,

3-methylbenzylhydrazine,

3-ethylbenzylhydrazine,

4-trifluoromethylbenzylhydrazine,

4-methyl-3-chlorobenzylhydrazine,

3-methyl-4-chlorobenzylhydrazine,

4-methyl-3-trifluoromethylbenzylhydrazine,

4-trifluoromethyl-3-chlorobenzylhydrazine,

4-chloro-3-trifluoromethylbenzylhydrazine,

4-sulphonamidobenzylhydrazine,

3-sulphonamido-4-chlorobenzylhydrazine,

4-methoxybenzylhydrazine,

5-hydrazinomethylindane,

2-hydrazinomethylnaphthalene,

2-hydrazinomethyl-5,6,7,8-tetrahydronaphthalene,

1-phenyl-3-hydrazino-prop-1-ene,

2-phenyl-4-hydrazino-but-2-ene,

1-phenyl-2-hydrazinomethyl-prop-1-ene, 1-phenyl-3-hydrazino-but-1-ene,

β-phenylethylhydrazine,

β-(3-chlorophenyl)-ethylhydrazine,

β -(3-bromophenyl)-ethylhydrazine,

β-(4-chlorophenyl)-ethylhydrazine,

β-(4-bromophenyl)-ethylhydrazine,

β-(3,4-dichlorophenyl)-ethylhydrazine,

β-(4-bromo-3-chlorophenyl)-ethylhydrazine,

β-(4-methylphenyl)-ethylhydrazine,

β-(4-trifluoromethylphenyl)-ethylhydrazine,

β-(3-chloro-4-methylphenyl)-ethylhydrazine,

[α-methyl-β-(3,4dichlorophenyl)-ethyl]-hydrazine,

[α-methyl-β-(3-chloro-4-methylphenyl)-ethyl]-hydrazine,

[α-ethyl-β-(3,4-dichlorophenyl)-ethyl]-hydrazine,

[α-n-propyl-β-(3,4-dichlorophenyl)-ethyl]-hydrazine,

[β-methyl-β-(3,4-dichlorophenyl)-ethyl]-hydrazine,

[β-methyl-β-(3-chloro-4-methylphenyl)-ethyl]-hydrazine,

[β-propyl-β-(3,4-dichlorophenyl)-ethyl]-hydrazine,

β-phenoxy-ethylhydrazine,

β-(3-chlorophenoxy)-ethylhydrazine,

β-(3-chloro-4-methylphenoxy)-ethylhydrazine,

[β-methyl-β-(3,5-dichlorophenoxy)-ethyl]-hydrazine,

[(α-ethyl-β-phenoxy)-ethyl]-hydrazine and

β-phenylmercaptoethylhydrazine.

Acetic acid derivatives of the formula VII, which are used as startingmaterials, are known from the literature or can be prepared by processesknown from the literature (compare Org. Synth., Coll. I, 249; Org.Synth., 41, 50; Cope, J. Amer. Chem. Soc., 67, 1047 (1947); C. C.Steele, J. Amer. Chem. Soc., 53, 286 (1931); A. H. Cook, J. Chem. Soc.(London) 1949, 3224).

Although referred to in this specification as acetic acid derivatives,the compounds of formula VII can perhaps more accurately be designatedat β-aminoacrylic acid derivatives when Y' and Y" together form themoiety ##STR13## cyanoacetic acid derivatives when Y is hydrogen and Y"is cyano, or as formylcarboxylic acid derivatives when Y' is hydrogenand Y" is --COH.

Representative acetic acid derivatives of the formula VII include:

cyanoacetic acid methyl ester,

cyanoacetic acid ethyl ester,

cyanoacetic acid propyl ester,

cyanoacetic acid isopropyl ester,

cyanoacetic acid n-butyl ester (compare Org. Synth. 41, page 5),

cyanoacetic acid isobutyl ester,

cyanoacetic acid t.-butyl ester,

cyanoacetic acid hexyl ester,

cyanoacetic acid benzyl ester,

cyanoacetic acid amide,

cyanoacetic acid methylamide,

cyanoacetic acid diethylamide,

cyanoacetic acid butylamide,

α-cyanopropionic acid methyl ester,

α-cyanopropionic acid ethyl ester,

α-cyanopropionic acid propyl ester,

α-cyanopropionic acid isopropyl ester,

α-cyanopropionic acid n-butyl ester,

α-cyanopropionic acid isobutyl ester,

α-cyanopropionic acid t.-butyl ester,

α-cyanopropionic acid hexyl ester,

α-cyanopropionic acid benzyl ester,

α-cyanopropionic acid amide,

α-cyanopropionic acid methylamide,

α-cyanopropionic acid diethylamide,

α-cyanopropionic acid butylamide,

α-cyanobutyric acid ethyl ester,

α-cyanobutyric acid t.-butyl ester,

α-cyanobutyric acid diethylamide,

α-cyano-β-phenylpropionic acid ethyl ester,

β-amino-β-methoxyacrylic acid ethyl ester,

β-amino-β-ethoxyacrylic acid ethyl ester,

β-amino-β-butoxyacrylic acid butyl ester,

β-amino-β-phenoxyacrylic acid ethyl ester,

β-amino-β-benzyloxyacrylic acid benzyl ester,

β-amino-β-ethoxyacrylic acid amide,

β-amino-β-ethoxyacrylic acid diethylamide,

β-amino-β-methylmercaptoacrylic acid ethyl ester,

β-amino-β-benzylmercaptoacrylic acid ethyl ester,

β-amino-β-methylmercaptoacrylic acid amide,

β,β -diaminoacrylic acid ethyl ester,

β,β -diaminoacrylic acid amide,

β-amino-β-methoxymethacrylic acid ethyl ester,

β-amino-β-ethoxymethacrylic acid ethyl ester,

β-amino-β-butoxymethacrylic acid butyl ester,

β-amino-β-phenoxymethacrylic acid ethyl ester,

β-amino-β-benzyloxmethacrylic acid ethyl ester,

β-amino-β-methylmercaptomethacrylic acid ethyl ester,

β-amino-β-benzylmercaptomethacrylic acid ethyl ester,

β-amino-β-ethoxymethacrylic acid amide,

β-amino-β-ethoxymethacrylic acid diethylamide,

β-amino-β-methylmercaptomethacrylic acid amide,

β,β-diaminomethacrylic acid ethyl ester,

β,β-diaminomethacrylic acid amide,

β-amino-β-ethoxy-α-ethylacrylic acid ethyl ester,

β-amino-β-methylmercapto-α-ethylacrylic acid ethyl ester,β-amino-β-ethoxy-α-ethylacrylic acid amide,

β-amino-β-ethoxy-α-phenylacrylic acid ethyl ester,

β-amino-β-ethoxy-α-benzylacrylic acid ethyl ester,

α-formylacetic acid ethyl ester,

α-formylpropionic acid ethyl ester,

α-cyano-β-phenylpropionic acid ethyl ester and

α-cyano-phenylacetic acid ethyl ester.

Diluents for use according to Process Variant A include all inertorganic solvents, which, when they are miscible with water, can also, ifdesired, be diluted with water. Preferred organic solvents includehydrocarbons (such as benzene, toluene and xylene), halogenatedhydrocarbons (such as methylene chloride, chloroform, carbontetrachloride and chlorobenzene), alcohols (such as methanol, ethanol,propanol, butanol, benzyl alcohol and glycol monomethyl ether), ethers(such as tetrahydrofuran, dioxane and glycol dimethyl ether), amides(such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone andhexamethylphosphoric acid triamide), sulphoxides (such asdimethylsulphoxide), sulphones (such as sulpholane) and base (such aspyridine, picoline, collidine, lutidine and quinoline).

As basic condensation agents in Process Variant A there may be usedinorganic and organic bases. Preferred bases for this purpose includealkali metal hydroxides (such as sodium hydroxide and potassiumcarbonate) and alcoholates (such as sodium alcoholate and potassiumalcoholate).

Alternatively there may be used as an acid catalyst, inorganic ororganic acid. Preferred acids include hydrogen halide acids, sulphuricacid and sulphonic acids (such as toluenesulphonic acid andtrifluoromethylsulphonic acid).

The reaction temperatures in Process Variant A can be varied over asubstantial range. In general, the reaction is carried out at atemperature of from 10° to about 200° C, preferably between 20° and 100°C. It can be carried out under atmospheric pressure but also in closedvessels at a higher pressure.

In carrying out the process according to the invention, 1 mol of thehydrazine VI and 1 mol of β-aminoacrylic acid derivative VII ##STR14##are reacted. It is possible to start either from the β-aminoacrylic acidderivative in the free form or from its acid addition salts. In thelatter case it is desirable to add 1 mol of a base in order to liberatethe β-aminoacrylic acid derivative. If the hydrazine derivative and theβ-aminoacrylic acid derivative are employed in the free form, theaddition of 1 to 10 % of an acid catalyst is desirable. Another possibleprocedure is to add a correspondingly smaller amount of a base to thereaction mixture for the purpose of neutralizing the salt ofβ-aminoacrylic acid derivative. When using the acid addition salt, thereaction can also be carried out by isolating the intermediateamidrazone of the formula: ##STR15## which are first produced and thencyclizing these in a second reaction step, thermally or by the action ofa basic condensation agent, to give the compounds of the invention.However, the one-stage synthesis is particularly advantageous.

In carrying out the process according to the invention as illustrated inequation A 2), 1 mol of the cyanoacetic acid derivative VII (Y' is H, Y"is cyano), and 1 to 3 mols, preferably 2 mols, of the basic condensationagent are employed per 1 mol of the hydrazine VI. With this procedure,the compounds of the present invention are obtained in the form of theirsalts and can be liberated by treatment with equivalent amounts of adilute acid. They can easily be purified by recrystallization from asuitable solvent or by dissolving them with dilute sodium hydroxidesolution, filtering the solution in the presence of animal charcoal andprecipitating the product by means of dilute acids.

If the process according to the present invention is carried out asillustrated in reaction scheme A 3), 1 mol of the hydrazine derivativeVI is reacted with 1 mol of the α-formylcarboxylic acid derivative VII##STR16## in a suitable diluent, the reaction mixture preferably beingstirred for two hours at an elevated temperature after completion of theexothermic initial reaction. The compounds of the present invention,which in most cases are obtained in a crystalline form can easily bepurified by recrystallization from a suitable solvent.

According to Process Variant B, A is preferably chlorine or bromine. Thehalogen compounds of formula VIII used in Process Variant B as startingsubstances are known from the literature or can be prepared by methodsknown from the literature (compare, for example, Houben-Weyl, Methodender organischen Chemie (Methods of Organic Chemistry), Volume V, 3(1962) and Volume V, 4 (1960)). The following halogen compounds VIIIwhich are representative of the starting materials which can be usedaccording to the present process include:

3-chlorobenzyl chloride,

3-bromobenzyl chloride,

4-chlorobenzyl chloride,

4-bromobenzyl chloride,

3,4-dichlorobenzyl chloride,

4 -bromo-3-chlorobenzyl chloride,

4-methylbenzyl chloride,

4-trifluoromethylbenzyl chloride,

3-chloro-4-methylbenzyl chloride,

4-chlorobenzylbromide,

3,4-dichlorobenzyl bromide,

3-chloro-4-methylbenzyl bromide,

γ-phenylallyl chloride,

β-phenylethyl chloride,

β-(3-chlorophenyl)-ethyl bromide,

β-(3,4-dichlorophenyl)-ethyl chloride,

β-(3-chloro-4-methylphenyl)-ethyl bromide,

β-(3,4-dichlorophenyl)-n-propyl chloride,

β-phenoxyethyl chloride,

β-phenoxy-n-propyl chloride,

β-phenoxy-n-butyl bromide,

β-phenylmercaptoethyl chloride and

β-phenylmercapto-n-butyl bromide.

The pyrazol-5-one derivatives of the formula IX used as startingcompounds in Process Variant B are known from the literature or can beprepared by methods known from the literature (compare, for example, B.Graham et al., J. Amer. Chem. Soc., 71, 983 (1949); R. Jones et al.Tetrahedron, 19, 1947 (1963)).

Representative pyrazol-5-ones of formula IX which can be used accordingto the process of the present invention include:

3-amino-pyrazol-5-one,

3-amino-4-methyl-pyrazol-5-one,

3-amino-4-butylpyrazol-5-one,

3-amino-4-phenylpyrazol-5-one,

3-amino-4-benzylpyrazol-5-one,

4-methylpyrazol-5-one,

4-phenylpyrazol-5-one and

4-benzylpyrazol-5-one.

Possible diluents for use in Process Variant B are all inert solvents.Preferred solvents include hydrocarbons (such as benzene, toluene andxylene), alcohols (such as methanol, ethanol, propanol, butanol, benzylalcohol and glycol monomethyl ether), ethers (such as tetrahydrofuran,dioxane and glycol dimethyl ether), amides (such as dimethylformamideand dimethylacetamide, N-methylpyrrolidone, and hexamethylphoshoric acidtriamide), sulphoxides (such as dimethylsulphoxide) and sulphones (suchas sulpholane).

Bases which can be used in Process Variant B include in principle, allinorganic and organic ides, carbonates, alcoholates, hydrides andamides.

The reaction temperatures in Process Variant B can be varied over asubstantial range. Preferably, the reaction is carried out at atemperature of from 20° to about 120° C. It is generally carried outunder atmospheric pressure but one can also carry it out in a closedvessel at a higher pressure.

In carrying out Process Variant B, a salt is generally first preparedfrom one mol of the pyrazolone derivative IX in a suitable solvent bymeans of an equimolar amount of a base. One mol of the halogen compoundis added to a solution of this salt and the entire reaction mixture isstirred, preferably at an elevated temperature.

The compounds of the present invention are preferably isolated bydistilling off the solvent in vacuo, taking up the residue in water andrendering the aqueous mixture weakly acid. The compounds of the presentinvention obtained using this procedure can easily be purified byrecrystallization from a suitable solvent.

According to Process Variant C, Z is preferably chlorine or bromine.

The pyrazol-5-one derivatives of formula X used as starting compounds inProcess Variant C can be prepared in a simple manner by methods knownfrom the literature (compare, for example, Japanese Patent 2872 ('64)(1961) and G. Barnikow, Chem. Ber., 100, 1661 (1967)).

The following pyrazole-5-ones of formula X, wherein Z is chlorine orbromine, are representative of those which can be used according to theprocess of the present invention:

3-chloro-4-methyl-1-(3-chlorobenzyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(4-chlorobenzyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(4-bromobenzyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

3-bromo-4-methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(4-bromo-3-chlorobenzyl)-pyrazol-5-one,

3-chloro-4-phenyl-1-(4-bromo-3-chlorobenzyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(4-trifluoromethylbenzyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-bromo-4-methyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-chloro-4-benzyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-chloro-1-(γ-phenylallyl)-pyrazol-5-one,

3-chloro-1-(β-phenylethyl)-pyrazol-5-one,

3-bromo-1-(β-phenylethyl)-pyrazol-5-one,

3-chloro-4-methyl-1-(β-phenylethyl)-pyrazol-5-one,

3-chloro-1-(β-[-chlorophenyl]-ethyl)-pyrazol-5-one,

3-chloro-1-(β-[3,4-dichlorophenyl]-ethyl)-pyrazol-5-one,

3-chloro-1-(β-[3-chloro-4-methylphenyl]-ethyl)-pyrazol-5-one,

3-chloro-1-(β-phenoxyethyl)-pyrazol-5-one,

3-chloro-1-(β-phenoxy-n-propyl)-pyrazol-5-one and

3-chloro-1-(β-phenylmercaptoethyl)-pyrazol-5-one.

Possible diluents for use in Process Variant C are water and all inertorganic solvents which, where they are water-miscible, can be dilutedwith water. Preferred organic solvents include hydrocarbons (such asbenzene, toluene and xylene), alcohols (such as methanol, ethanol,propanol, butanol, benzyl alcohol and glycol monomethyl ether), andethers (such as tetrahydrofuran, dioxane and glycol dimethyl ether).

The reaction temperatures in Process Variant C can be varied over asubstantial range. The reaction is generally carried out at atemperature of from about 20° to 220° C, but preferably between 50° and150° C. It can be carried out either under atmospheric pressure or inclosed vessel at higher pressures.

In carrying out Process Variant C, one mol of the pyrazolone derivativeX is generally reacted with a twofold to twenty-fold, preferablytenfold, excess of ammonia.

The procedure followed is preferably that the reactants, optionally inan inert solvent, are reacted in a closed vessel at an elevatedtemperature. The compounds of the present invention, thus obtained, caneasily be purified by recrystallization from a suitable solvent.

According to process Variant D, Z¹ is preferably straight orbranched-chain alkyl of 1 to 6 carbon atoms, especialy t-butyl, or aphenyl or benzyl. The pyrazol-5-one of formula XI is hydrolyzed with aninorganic or organic acid such as a hydrogen halode acid, sulphuricacid, phosphoric acid, acetic acid, trifluoroacetic acid or a mixture oftwo or more thereof with a base such as an alkali metal hydroxide oralkali earth metal hydroxide as above described.

The pyrazol-5-one derivatives of the formula XI used as startingcompounds have not hitherto been disclosed but can be prepared bymethods known from the literature, for example, by reacting thecarboxylic acid of the formula XIII, wherein R¹, R² and X are as abovedefined, ##STR17## which in turn can be obtained by hydrolysis of thecorresponding esters which can be prepared from optionally substitutedoxalacetic acid esters and hydrazines of the formula IV according to amodified Curtius reaction with diphenylphosphoryl azide (T. Schioiri etal., J. Amer. Chem. Soc., 94, 6203 (1972)) or by Weinstock's method (J.Org. Chem., 26, 3511 (1961)).

The following pyrazol-5-ones of the formula XI are representative ofthose which may be used according to the process of the presentinvention:

3-carbo-ethoxyamino-4-methyl-1-(3-chlorobenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-methyl-1-(4-chlorobenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-methyl-1-(4-bromobenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-4-methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

3-carbo-n-propoxyamino-4-methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-methyl-1-(4-bromo-3-chlorobenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-methyl-1-(4-trifluoromethylbenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-methyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-4-methyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-phenyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-carboethoxyamino-4-benzyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-carboethoxyamino-1-(γ-phenylallyl)-pyrazol-5-one,

3-carboethoxyamino-1-(β-phenylethyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-1-(β-phenylethyl)-pyrazol-5-one,

3-carbobenzyloxyamino-1-(β-phenylethyl)-pyrazol-5-one,

3-carbophenoxyamino-1-(β-phenylethyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-1-(β-[3-chlorophenyl)]-ethyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-1-(β-[3,4-dichlorophenyl]-ethyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-1-(β-(3-chloro-4-methylphenyl]-ethyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-1-(β-phenoxyethyl)-pyrazol-5-one,

3-carbo-t.-butoxyamino-1-(β-phenoxy-n-propyl)-pyrazol-5-one and

3-carbo-t.-butoxyamino-1-(β-phenylmercaptoethyl)-pyrazol-5-one.

Possible diluents for use in Process Variant D are water andwater-miscible inert organic solvents. Preferred solvents includealcohols (such as methanol, ethanol, propanol, ethylene glycol andglycol monomethyl ether), and ethers (such as tetrahydrofuran ordioxane).

The reaction temperatures in Process Variant D can be carried over asubstantial range. Preferably, the reaction is carried out at atemperature of from about 70° to about 150° C. Normally the reaction iscarried out under atmospheric pressure, but it can also be carried outin closed vessels at higher pressure.

In carrying out Process Variant D, an aliquot part of the pyrazolonederivative XI, optionally in an inert solvent, is generally stirredwith, preferably, a fivefold to twenty-five-fold excess of an aqueoussolution of an acid or a base at an elevated temperature. The compoundsof the present invention precipitate after neutralization of thereaction solution and can easily be purified by recrystallization from asuitable solvent.

According to Process Variant E, Z² is preferably hydroxy, straight orbranched-chain alkoxy of 1 to 6 carbon atoms, especially methoxy orethoxy, benzyloxy or amino or alkylamino or dialkylamino of 1 to 4carbon atoms in each alkyl moiety.

The acetylenecarboxylic acid derivatives of the formula XII used asstarting compounds in Process Variant E are known from the literature orcan be prepared by methods known from the literature. (Compare, forexample, Beilstein's Handbuch der organischen Chemie (Handbook ofOrganic Chemistry) 2, III, 1,447 et seq. (1961) and 9, III, 3,061 et seq(1971)).

Representative acetylenecarboxylic acids of the formula XII which may beused according to the process of the present invention include:

propiolic acid ethyl ester,

propiolic acid n-butyl ester,

propiolic acid isopropyl ester,

propiolic acid benzyl ester,

propiolic acid amide,

propiolic acid dimethylamide,

propiolic acid ethylamide,

propiolic acid n-butylamide and

propiolic acid diethylamide.

The hydrazines VI used in Process Variant E are the same as those usedin Process Variant A, q.v.

Possible diluents for use in Process Variant E are all inert organicsolvents which, where they are watermiscible, can be diluted with water.Preferred organic solvents include hydrocarbons (such as benzene,toluene and xylene), halogenated hydrocarbons (such as methylenechloride, chloroform, carbon tetrachloride and chlorobenzene), alcohols(such as methanol, ethanol, propanol, butanol, benzyl alcohol and glycolmonomethyl ether), ethers (such as tetrahydrofuran, dioxane and glycoldimethyl ether), amides (such as dimethylformamide, dimethylacetamide,N-methyl-pyrrolidone and hexamethylphosphoric acid triamide),sulphoxides (such as dimethylsulphoxide), sulphones (such as sulpholane)and bases (such as pyridine, picoline, collidine, lutidine andquinoline).

The reaction temperatures in Process Variant E can be varied within asubstantial range. In general, the reaction is carried out at atemperature of from about 50° to about 200° C, preferably between 70°and 150° C. It is carried out under atmospheric pressure but can also becarried out in closed vessels at a higher pressure.

In carrying out Process Variant E, 1 mol of the acetylenecarboxylic acidderivative XII, optionally in a suitable diluent, is generally reactedwith 1 mol of the hydrazine VI. The compounds of the present invention,which, in most cases, are obtained in a crystalline form, if necessaryafter evaporating off the diluent, can easily be purified byrecrystallizaton from a suitable solvent.

The quantities mentioned in Process Variants A to E can, of course, bevaried slightly.

The following compounds are representative of those of the presentinvention:

1-(β-3-methylphenylmercapto)-ethyl)-pyrazol-5-one,

1-(β-phenethyl)-pyrazol-5-one,

4-methyl-1-(β-phenoxyethyl)-pyrazol-5-one,

4-methyl-1-(β-(3-chlorophenoxy)-ethyl)-pyrazol-5-one,

4-methyl-1-(β-(3-methylphenoxy)-ethyl)-pyrazol-5-one,

4-methyl-1-(β-(3,4-dichlorophenoxy)-ethyl)-pyrazol-5-one,

4-methyl-1-(β-(3,5-dichlorophenoxy)-ethyl)-pyrazol-5-one,

4-methyl-1(β-(3-trifluoromethoxyphenoxy)-ethyl)-pyrazol-5-one,

4-methyl-1-(β -(3-ethylphenoxy)-ethyl)-pyrazol-5-one,

4-ethyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

4-ethyl-1-(β-(3-chlorophenoxy)-ethyl)-pyrazol-5-one,

4-phenyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one,

4-phenyl-1-(β-phenoxyethyl)-pyrazol-5-one,

4-phenyl-1-(β-(3-chlorophenoxy)-ethyl)-pyrazol-5-one,

4-benzyl-1-(3-chlorobenzyl)-pyrazol-5-one,

4-benzyl-1-(4-chlorobenzyl)-pyrazol-5-one,

4-benzyl-1-(β-phenoxyethyl)-pyrazol-5-one,

4-methyl-1-(γ-(3-chloropenyl)-allyl)-pyrazol-5-one,

4 -methyl-1-(α-methyl-γ-phenylallyl)-pyrazol-5-one,

3-amino-1-(γ-(3,4-dichlorophenyl)-allyl)-pyrazol-5-one,

3-amino-1-(β-methyl-γ-phenyl)-allyl)-pyrazol-5-one,

4-methyl-1-(3-chloro-4-methylbenzyl)-pyrazol-5-one,

3-amino -1-(β-(2-methylphenoxy)-ethyl-pyrazol-5-one,

3-amino-1-(β-(2-chlorophenoxy)-ethyl)-pyrazol-5-one,

3-amino-1-(α-methyl-β-phenoxyethyl)-pyrazol-5-one,

3-amino-1-(α-methyl-β-(3-chloro-4-methylphenoxy)-ethyl)-pyrazol-5-one,

3-amino-1-(β-methyl-β-(4-cyclohexylphenoxy)-ethyl)-pyrazol-5-one,

3-amino-1-(β-(2-nitrophenoxy)-ethyl)-pyrazol-5-one,

3-amino-1-(β-ethyl-β-(4-isopropylphenoxy)-ethyl)-pyrazol-5-one,

3-amino-1-(β-(naphthyl-(2)-oxy)-ethyl)-pyrazol-5-one,

3-amino-1(β-methyl-β-(4-methylphenylmercapto)-ethyl)-pyrazol-5-one,

3-amino-1-(β-(naphthyl-(2)-mercapto)-ethyl)-pyrazol-5-one,

3-amino-1-(β-(3,4-trimethylenephenyl)-ethyl)-pyrazol-5-one,

3-amino-1-(β-(4-chlorophenyl)-ethyl)-pyrazol-5-one,

3-amino-1-(α,β-dimethyl-β-phenylethyl)-pyrazol-5-one,

3-amino-1-(β-methyl-β-(3-chloro-4-methylphenyl)-ethyl)-pyrazol-5-one,

3-amino-1-(α-ethyl-β-phenylethyl)-pyrazol-5-one,

3-amino-4 -methyl-1-(3-chlorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3-bromobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-bromobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3-fluorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-fluorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-iodobenzyl)-pyrazol-5-one,

3-amino-4 -methyl-1-(4-chloro-3-bromobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-bromo-3-chlorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-fluoro-3-chlorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3,4-dibromobenzyl)-pyrazol-5-one,

3-amino-4-methyl- 1-(4-methylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4 -isopropylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-n-butylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-cyclohexylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-trifluoromethylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-methyl-3-chlorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3-methyl-4-chlorobenzyl)-pyrazol-5-one,

3-amino- 4-methyl-1-(4-trifluoromethyl-3-chlorobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-methyl-3-trifluoromethylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-chloro-3-trifluoromethylbenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-nitrobenzyl)-pyrazol-5-one,

3-amino- 4-methyl-1-(4-sulphonamidobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3-sulphonamido-4-chlorobenzyl)-pyrazol-5-one,

3 -amino-4 -methyl-1-(4-methoxybenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-isopropyloxybenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-trifluoromethoxybenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(4-dimethylaminobenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3,4-trimethylenebenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(3,4-tetramethylenebenzyl)-pyrazol-5-one,

3-amino-4-methyl-1-(α-benzyl-n-propyl)-pyrazol-5-one,

3-amino-4-methyl-1-(α,β-dimethyl-β-phenylethyl)-pyrazol-5-one,

3-amino-4-methyl-1-(β-methyl-β-phenoxyethyl)-pyrazol-5-one and,

3-amino-4-methyl-1-(β-(naphthyl-(2)-oxy)-ethyl)-pyrazol-5-one.

The compounds of the present invention are particularly useful for oralor parenteral administration in effecting diuresis and saluresis and cantherefore be used for the treatment of oedematous and hypertonicconditions and for flushing out toxic substances.

Representative pyrazol-5-ones of the present invention were tested andthe following data is representative of the diuretic and salureticactivity of the compounds of the present invention.

Diuresis experiment with dogs

a. Method

Beagle bitches were used.

On the day of the experiment, the animals were given 1 ml/kg of asolution which contained 0.4% of NaCl and 0.2% of KCl every 30 minutesby means of a probang. Thereafter, the test preparation was administeredorally and the change in excretion of electrolyte was measured in theurine in comparison with control groups. The amounts of urine wereconverted to ml/kg. It was then possible to calculate the excretion inμequivalents/kg from the volume of urine and the measured electrolyteconcentration. Sodium and potassium were determined by flame photometry.

b. Results

The results are shown in Table I. The renal excretion of sodium andwater was increased substantially after oral administration of the testpreparation. The effect depended on the dose.

                                      Table I                                     __________________________________________________________________________    Excretion in μequivalent or ml/kg/l hour                                                                  Na.sup.+                                                                            k.sup.+                                                                           H.sub.2 O                            __________________________________________________________________________    Control                        140   152 2.0                                   ##STR18##               3 mg/kg                                                                             326   290 2.6                                   ##STR19##               3mg/kg                                                                              1.637 218 14.9                                  ##STR20##               3 mg/kg                                                                             637   319 5.7                                  __________________________________________________________________________

The pharmaceutical compositions of the present invention contain a majoror minor amount, e.g., 0.1 to 99.5%, preferably 0.5 to 90%, of activeingredient as above defined in combination with pharmaceuticallyacceptable, nontoxic, inert diluent or carrier, the carrier comprisingone or more solid, semi-solid or liquid diluent, filler and formulationadjuvant which is nontoxic, inert and pharmaceutically acceptable. Suchpharmaceutical compositions are preferably in dosage unit form; i.e.,physically discrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three, four or more single doses or, alternatively,one half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three orfour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the dosage forparenteral administration will be from 0.01 to 50, and preferably 0.1 to10 mg/kg of body weight per day, whereas the oral dosage will be 0.1 to500, and preferably 0.5 to 100 mg/kg of body weight per day. In someinstances a sufficient therapeutic effect can be obtained at a lowerdose, while in others, a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitable comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet-formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free-flowing, inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitfoms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting, water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample myristyl palmitate, or mixtures thereof.

The preferred daily dose for parenteral administration is 0.5 mg to 50g, particular 5 mg to 1 g, of active agent; for oral administration thepreferred daily dosage of active agent is 5 mg to 50 g, particularly 25mg to 10 g.

While the routes of administration include oral parenteral (i.e.,intramuscular, intraperitoneal, and intravenous), and rectal, oraladministration and parenteral administration are particularly preferred.

The preferred pharmaceutical compositions are therefore those in a formsuitable for oral administration such as tablets and suspensions andthose suitable for parenteral administration such as solutions andsuspensions.

Examples A and B set forth below are illustrative of pharmaceuticalcompositions embodying the compounds of the present invention:

EXAMPLE A

200 g of 3-amino-4 -methyl-1-(3-chlorobenzyl)-pyrazol-5-one arecomminuted to a powder and mixed with 300 g of lactose and 200 g ofpotato starch, and after moistening with an aqueous gelatine solutionthe mixture is granulated through a sieve. After drying, 60 g of talcand 5 g of sodium lauryl sulphate are added and 10,000 tablets eachcontaining 20 mg of active compound are pressed from the mixture.

EXAMPLE B

20 g of the sodium salt of 3-amino-4-methyl-1-(4-chlorobenzyl)-pyrazol-5-one are dissolved in 1,000 ml of propyleneglycol and the solution is made up to 2,000 ml with water. This solutionis filled under aseptic conditions into sterile ampoules each of 5 mlcapacity and each containing 50 mg of active compound.

The following Preparative Examples describe by way of illustration onlythe production of certain compounds of the invention using the processof the invention.

EXAMPLE 1 (4-Methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one, by ProcessVariant A). ##STR21##

10.9 g of 3,4-dichlorobenzylhydrazine were added dropwise to a solutionof 7.5 g of α-formylpropionic acid ethyl ester in 50 ml of ethanol.After stirring overnight at room temperature, the solvent was distilledoff in vacuo and the solid residue was recrystallized from ethanol.

Melting point 156° C; yield 9.3 g (64%).

EXAMPLE 2 (4-Methyl-1-(3,4-dichlorobenzyl)-pyrazol-5-one, by ProcessVariant B).

19.6 g of 4-methylpyrazol-5-one were added in portions to a suspensionof 5.0 g of sodium hydride in 100 ml of absolute dimethylformamide.After the evolution of H₂ had ceased, 39 g of 3,4-dichlorobenzylchloride were added dropwise to the reaction solution.

The mixture was then stirred for 2 hours at 60° C, the solvent wasdistilled off in vacuo, the residue was taken up in water and themixture was acidified with dilute acetic acid. The crude product therebyobtained was recrystallized from ethanol.

Melting point 155°-157° C; yield 13 g (25%)

EXAMPLE 3 (3-Amino-1-(β-phenylethyl)-pyrazol-4-one). ##STR22##

A pinch of p-toluenesulphonic acid was added to 23.7 g ofβ-amino-β-ethoxyacrylic acid ethyl ester in 150 ml of tetrahydrofuranand 20.4 g of phenylethylhydrazine were then added under nitrogen.

The reaction mixture was stirred overnight under N₂ at 40° C and wasthen concentrated in vacuo. The oily residue was dissolved in a little 2N sodium hydroxide solution. Any starting material still present, andby-products, were extracted from the aqueous phase with ether.

The aqueous phase was clarified with charcoal, acidified with aceticacid (pH 5) and thoroughly shaken with methylene chloride. The methylenechloride phase was dried with sodium sulphate and concentrated, giving acrystalline product which was recrystallized from ethanol.

Melting point 162°-164° C; yield 14 g (42%)

The compounds shown in the table which follows were obtained analogouslyto Example 3:

    __________________________________________________________________________                                  Recrystallization                                                                      Yield, %                                                                            Melting point                    No.     Structural formula    from     of theory                                                                           ° C                       __________________________________________________________________________         ##STR23##                Ethanol  71.5  77-79                                From: 3-trifluorophenylethylhydrazine + (x)*                              5                                                                                  ##STR24##                Ethanol  65    126-128                              From: 3-chlorophenylethylhydrazine + (x)*                                 6                                                                                  ##STR25##                Ethanol  69    127-129                              From: 4-methylphenylethylhydrazine + (x)*                                 7                                                                                  ##STR26##                Methanol 48    130-132                              From: γ-phenyl-allylhydrazine + (x)*                                __________________________________________________________________________     (x)* = β-amino-β-ethoxyacrylic acid ethylester                 

EXAMPLE 8 (3-Amino-1-(α-methyl-β-(2-chlorophenoxy)-ethyl)-pyrazol-5-one)##STR27##

A mixture of 31.8 g of β-amino-β-ethoxyacrylic acid ethyl ester, 150 mlof absolute ethanol, 42 g of α-methyl-β-(3-chlorophenoxy)-ethylhydrazineand a pinch of p-toluenesulphonic acid was stirred overnight undernitrogen at room temperature and then concentrated in vacuo. The residuewas triturated with a little ether. Hereupon, the crude solidcrystallized out. It was recrystallized from methanol.

Melting point 158°-160° C; yield 23 g (43%)

The compounds shown in the table which follows were obtained analogouslyto Example 8:

    __________________________________________________________________________                                    Recrystallization                                                                      Yield, %                                                                            Melting Point                  No.     Structural formula      from     of theory                                                                           ° C                     __________________________________________________________________________     9                                                                                 ##STR28##                  Ethanol  51    130-132                            From: phenoxy-ethylhydrazine + (x)*                                       10                                                                                 ##STR29##                  Ethanol   46.5 124-126                            From: 3,4-di-methylphenoxy-ethylhydrazine + (x)*                          11                                                                                 ##STR30##                  Ethanol  54    91-93                              From: 3-methyl-5-ethylphenoxy-ethylhydrazine + (x)*                       12                                                                                 ##STR31##                  Methanol 44    124-126                            From: 3-methylphenoxy-ethylhydrazine + (x)*                               13                                                                                 ##STR32##                  Methanol 61    149-151                            From: 4-methylphenoxy-ethylhydrazine + (x)*                               14                                                                                 ##STR33##                  Methanol 55    115-117                            From: 4-chlorophenylthio-ethylhydrazine + (x)*                            15                                                                                 ##STR34##                  Ethanol  51    100-102                            From: phenylthio-ethylhydrazine + (x)*                                    __________________________________________________________________________     (x)* = β-amino-βethoxyacrylic acid ethyl ester                 

EXAMPLE 16

(same compound as Example 12; Process Variant A) ##STR35##

A mixture of 22.6 g of cyanoacetic acid ethyl ester and 33.2 g ofβ-(3-methylphenoxy)-ethylhydrazine in 100 ml of ethanol was added to asolution of 9.2 g of sodium in 200 ml of ethanol at room temperature.The reaction mixture was then warmed to 60° C for 2 hours, the solventwas distilled off in vacuo and the residue was taken up in water. Afterextraction with ether, the aqueous phase was acidified with diluteacetic acid, whereupon the crude product precipitated. This was twicerecrystallized from ethanol.

Melting point 124°-126° C; yield 15 g (32%)

EXAMPLE 17 (3-Amino-4-methyl-1-(4-chlorobenzyl)-pyrazol-5-one).##STR36##

31.2 g of p-chlorobenzylhydrazine were added dropwise under nitrogen toa solution of 34.6 g of β-amino-β-ethoxymethacrylic acid ethyl ester anda pinch of p-toluenesulphonic acid in 200 ml of ethanol, whereupon thetemperature rose from 21° to 31° C. After standing overnight, theproduct which had precipitated was filtered off and recrystallized fromethanol.

Melting point 174° C; yield 22 g (46%)

The compounds shown in the table which follows were prepared analogouslyto the procedure described in Example 17:

    __________________________________________________________________________                              Recrystallization                                                                       Yield, %                                                                            Melting point                       No.                                                                              Structural formula     from      of theory                                                                           ° C                          __________________________________________________________________________    18                                                                                ##STR37##             Ethanol   54    147                                    From: 3,4-di-chlorobenzylhydrazine + (y)*                                  19                                                                                ##STR38##             Ethanol   43    120                                    From: thyl-methylhydrazine + (y)*                                          20                                                                                ##STR39##             Ethanol   40    126                                    From: phenoxyethylhydrazine + (y)*                                         __________________________________________________________________________     (y)* = β-amino-β-ethoxy-methacrylic acid ethyl ester           

EXAMPLE 21 (same compound as Example 17; Process Variant A) ##STR40##

A mixture of 25.4 g of α-cyanopropionic acid ethyl ester and 31.2 g of4-chlorobenzylhydrazine in 100 ml of ethanol was added to a solution of9.2 g of sodium in 200 ml of ethanol at room temperature. The reactionmixture was then warmed to 60° C for 2 hours, the solvent was distilledoff in vacuo and the residue was taken up in water. After extractionwith ether, the aqueous phase was acidified with dilute acetic acid andthe crude product which precipitated was twice recrystallized fromethanol.

Melting point 172°-174° C; yield 12 g (25%)

EXAMPLE 22 (3-Amino-4-n.-butyl-1-(3,4-dichlorobenzyl)-pyrazol5-one)##STR41##

36.5 g of 3,4-dichlorobenzylhydrazine were added dropwise under nitrogento a solution of 41.4 g of α-n.-butyl-β-amino-β-ethoxyacrylic acid ethylester and a pinch of p-toluenesulphonic acid in 100 ml of ethanol. Afterstirring for a further two hours, the mixture was left to standovernight. The solvent was distilled off and a 1:1 mixture of ether andpetroleum ether was added to the residue, whereupon the productcrystallized through.

Melting point 102° C; yield 22 g (37%)

The compounds shown in the table which follows were obtained analogouslyto Example 22:

    __________________________________________________________________________                                    Recrystallization                                                                      Yield, %                                                                            Melting point                  No.     Structural formula      from     of theory                                                                           ° C                     __________________________________________________________________________    23                                                                                 ##STR42##                  Ethanol  32    109                                From phenoxyethylhydrazine + (z)*                                         24                                                                                 ##STR43##                  Ethanol  17    154                                From: 3,4-di-chlorobenzylhydrazine + (z)*                                 __________________________________________________________________________     (z)* = α-sec.-butyl-β-amino-β-ethoxyacrylic acid ethyl        ester                                                                    

EXAMPLE 25(3-Amino-4-phenyl-1-(3-trifluoromethyl-4-methylbenzyl)-pyrazol-5-one).##STR44##

31.5 g of 3-trifluoromethyl-4-methylbenzylhydrazine were added dropwiseunder nitrogen to a solution of 35.3 g of α-phenyl-β-ethoxyacrylic acidethyl ester and 1 g of p-toluenesulphonic acid in 150 ml of ethanol.After stirring overnight, the solvent was distilled off in vacuo and theresidue was recrystallized from dimethylformamide.

Melting point 211° C; yield 22 g (42%)

The compound shown in the table which follows was obtained analogouslyto Example 25:

    __________________________________________________________________________                                  Recrystallization                                                                      Yield, %                                                                            Melting point                    No.    Structural formula     from     of theory                                                                           ° C                       __________________________________________________________________________    26                                                                                 ##STR45##                Ethanol  40    190                              phenyl-β-amino-β-ethoxyacrylic acid ethyl ester                     __________________________________________________________________________

EXAMPLE 27 (1-(4-chloro-benzyl)-pyrazol-5-one) ##STR46##

9.8 g (0.1 mol) of propiolic acid ethyl ester and 15.6 g (0.1 mol) ofp-chlorobenzylhydrazine in 100 ml of n-butanol were heated for 8 hoursunder reflux.

The solution was concentrated and the oily residue was triturated with amixture of ethanol and ether whereupon the reaction product crystallizedout. It was recrystallized from ethanol.

Melting point 146°-148° C. Yield 7.5 g (35% of theory).

EXAMPLE 28 (3-Amino-1-(β-(naphthyl-(2)-oxy)-ethyl-pyrazol-5-one)##STR47##

40 ml of glacial acetic acid were added to 0.1 mol of1-(β-(naphthyl-(2)-oxy)-ethyl)-3-ethoxycarbonylamino-pyrazolone-(5) in200 ml of aqueous 2 N hydrochloric acid and the mixture was then boiledfor 2 hours under reflux. After cooling, and neutralising with dilutesodium hydroxide solution, it was possible to filter off a crystallineproduct. This was recrystallized from methanol.

Melting point 133°-135° C; yield 20.2 g (75% of theory).

What is claimed is:
 1. A pharmaceutical composition useful for effectingdiuresis or saluresis in humans and animals and for treatinghypertension in humans and animals which comprises a diureticallyeffective amount, a saluretically effective amount or anantihypertensive amount of a compound of the formula ##STR48## or apharmaceutically acceptable nontoxic salt thereof, wherein R is amino;R¹is hydrogen, lower alkyl or lower alkenyl; X isethylene, ethylenewherein 1 hydrogen atom on 1 of the carbon atoms is substituted by alkylof 1 to 4 carbon atoms or ethylene wherein 1 hydrogen atom on each ofthe two carbon atoms is substituted by alkyl of 1 to 4 carbon atoms,linked to R² via an oxygen or sulphur atom; R² is aryl of 6 to 10 carbonatoms unsubstituted or substituted by:a. 1 or 2 of the same or differentsubstituents selected from the group consisting of halogen,trifluoromethyl, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbonatoms and lower alkoxy; b. cycloalkyl of 5, 6 or 7 carbon atoms orcycloalkenyl of 5,6 or 7 carbon atoms; c. nitro or d. nitro, and 1 or 2of the same or different substituents selected from the group consistingof lower alkyl, lower alkenyl, lower alkoxy, halogen andtrifluoromethylin combination with a pharmaceutically-acceptable,nontoxic, inert diluent or carrier.
 2. A composition according to claim1 whereinR² is aryl of 6 to 10 carbon atoms unsubstituted or substitutedby:a. 1 or 2 of the same or different substituents selected from thegroup consisting of halogen, trifluoromethyl, alkyl of 1 to 4 carbonatoms, alkenyl of 2 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms;b. nitro or c. nitro, and 1 or 2 of the same or different substituentsselected from the group consisting of alkyl of 1 to 4 carbon atoms,alkenyl of 2 to 4 carbon atoms, alkoxy of 2 to 4 carbon atoms, halogenand trifluoromethyl.
 3. A composition according to claim 1 whereinR¹ ishydrogen, alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbonatoms; and R² is phenyl; naphthyl; or phenyl substituted by:a. 1 or 2straight or branched-chain alkyl moieties of 1 to 8 carbon atoms, oralkenyl moieties of 2 to 8 carbon atoms; b. 1 or 2 alkoxy moieties of 1to 6 carbon atoms; c. cycloalkyl of 5, 6 or 7 carbon atoms orcycloalkenyl of 5, 6 or 7 carbon atoms; d. 1 or 2 halogens; e. 1 or 2trifluoromethyl moieties; or f. nitro.
 4. A composition according toclaim 1 whereinR¹ is hydrogen, alkyl of 1 to 4 carbon atoms or alkenylof 2 to 4 carbon atoms; and R² is phenyl; naphthyl; or phenylsubstituted by:a. 1 or 2 straight or branched-chain alkyl moieties of 1to 4 carbon atoms or alkenyl moieties of 2 to 4 carbon atoms; b. 1 or 2alkoxy moieties of 1 to 4 carbon atoms; c. cycloalkyl of 5, 6 or 7carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms; d. 1 or 2fluoro, chloro or bromo moieties; e. 1 or 2 trifluoromethyl moieties; orf. nitro.
 5. A composition according to claim 1 whereinR¹ is hydrogen,alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and R²is phenyl; naphthyl; or phenyl substituted by:a. 1 or 2 members selectedfrom the group consisting of straight or branched-chain alkyl andtrifluoromethyl moieties of 1 to 4 carbon atoms; b. alkoxy of 1 to 4carbon atoms; c. cycloalkyl of 5 or 6 carbon atoms; d. 1 or 2 fluoro,chloro, bromo or iodo moieties; e. chloro or bromo and alkyl of 1 or 2carbon atoms, trifluoromethyl; or f. nitro.
 6. A composition accordingto claim 1 whereinR¹ is hydrogen, methyl or ethyl; X is ethylene,ethylene wherein 1 hydrogen atom on one of the carbon atoms issubstituted by alkyl of 1 or 2 carbons or ethylene wherein 1 hydrogenatom on each of the two carbon atoms are substituted by alkyl of 1 or 2carbon atoms, linked to R² via an oxygen or sulphur atom; and R² isphenyl; naphthyl; or phenyl substituted by fluorine, chlorine, bromine,iodine, trifluoromethyl, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of1 to 4 carbon atoms, cyclohexyl, dichlorine, chlorine and methyl,chlorine and bromine, chlorine and fluorine, chlorine andtrifluoromethyl, dibromine or methyl and trifluoromethyl.
 7. Acomposition according to claim 6 whereinX is ethylene, ethylene where 1hydrogen on one of the carbon atoms is substituted by methyl or ethyl orethylene wherein 1 hydrogen atom on each of the two carbon atoms issubstituted by methyl, linked to R² via an oxygen or sulphur atom.
 8. Acomposition according to claim 1 whereinR¹ is hydrogen or alkyl of 1 to4 carbon atoms; X is ethylene or ethylene wherein 1 hydrogen atom on oneof the carbon atoms is substituted by methyl, linked to R² via an oxygenor sulphur atom; and R² is phenyl; naphthyl; or phenyl substituted by 1or 2 chlorine, methyl, ethyl or trifluoromethyl moieties.
 9. Acomposition according to claim 1 whereinR¹ is hydrogen or alkyl of 1 to4 carbon atoms; X is ethylene or ethylene wherein 1 hydrogen atom of oneof the carbon atoms is substituted by methyl, linked to R² via an oxygenor sulphur atom; and R² is naphthyl; phenyl; or phenyl substituted bychlorine, methyl, trifluoromethyl, dichlorine, dimethyl, methyl andethyl or methyl and trifluoromethyl.
 10. A composition according toclaim 1 wherein the compound is ##STR49##
 11. A composition according toclaim 1 wherein the compound is ##STR50##
 12. A composition according toclaim 1 wherein the compound is ##STR51##
 13. A composition according toclaim 1 wherein the compound is ##STR52##
 14. A composition according toclaim 1 wherein the compound is ##STR53##
 15. A composition according toclaim 1 wherein the compound is ##STR54##
 16. A composition according toclaim 1 wherein the compound is ##STR55##
 17. A composition according toclaim 1 wherein the compound is ##STR56##
 18. A composition according toclaim 1 wherein the compound is ##STR57##
 19. A composition according toclaim 1 wherein the compound is ##STR58##
 20. A composition according toclaim 1 wherein the compound is ##STR59##
 21. A method of effectingdiuresis and saluresis in humans and animals and treating hypertensionin humans and animals which comprises administering to such human oranimal a diuretically effective amount, a saluretically effective amountor an antihypertensive amount of a compound of the formula or apharmaceutically acceptable nontoxic salt thereof, whereinR is amino; R¹is hydrogen, lower alkyl or lower alkenyl; X is ethylene, ethylenewherein 1 hydrogen atom on 1 of the carbon atoms is substituted by alkylof 1 to 4 carbon atoms or ethylene wherein 1 hydrogen atom on each ofthe two carbon atoms is substituted by alkyl of 1 to 4 carbon atoms,linked to R² via an oxygen or sulphur atom; R² is aryl of 6 to 10 carbonatoms unsubstituted or substituted by:a. 1 to 2 of the same or differentsubstituents selected from the group consisting of halogen,trifluoromethyl, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbonatoms and lower alkoxy; b. cycloalkyl of 5, 6 or 7 carbon atoms orcycloalkenyl of 5, 6 or 7 carbon atoms; c. nitro; or d. nitro and 1 or 2of the same or different substituents selected from the group consistingof lower alkyl, lower alkenyl, lower alkoxy, halogen andtrifluoromethyl;in combination with a pharmaceutically-acceptable,nontoxic, inert diluent or carrier.
 22. A method according to claim 21whereinR² is aryl of 6 to 10 carbon atoms unsubstituted or substitutedby:a. 1 or 2 of the same or different substituents selected from thegroup consisting of halogen, trifluoromethyl, alkyl of 1 to 4 carbonatoms, alkenyl of 2 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms;b. nitro; or c. nitro and 1 or 2 of the same or different substituentsselected from the group consisting of alkyl of 1 to 4 carbon atoms,alkenyl of 2 to 4 carbon atoms, alkoxy of 2 to 4 carbon atoms, halogenand trifluoromethyl.
 23. A method according to claim 21 whereinR¹ ishydrogen, alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbonatoms; and R² is phenyl; naphthyl; or phenyl substituted by:a. 1 or 2straight or branched-chain alkyl moieties of 1 to 8 carbon atoms, oralkenyl moieties of 2 to 8 carbon atoms; b. 1 or 2 alkoxy moieties or 1to 6 carbon atoms; c. cycloalkyl of 5, 6 or 7 carbon atoms orcycloalkenyl of 5, 6 or 7 carbon atoms; d. 1 or 2 halogens; e. 1 or 2trifluoromethyl moieties; or f. nitro.
 24. A method according to claim21 whereinR¹ is hydrogen, alkyl of 1 to 4 carbon atoms or alkenyl of 2to 4 carbon atoms; and R² phenyl; naphthyl; or phenyl substituted by:a.1 or 2 straight or branched-chain alkyl moieties of 1 to 4 carbon atomsor alkenyl moieties of 2 to 4 carbon atoms; b. 1 or 2 alkoxy moieties of1 to 4 carbon atoms; c. cycloalkyl of 5, 6 or 7 carbon atoms orcycloalkenyl of 5, 6 or 7 carbon atoms; d. 1 or 2 fluoro, chloro orbromo moieties; e. 1 or 2 trifluoromethyl moieties; or f. nitro.
 25. Amethod according to claim 21 whereinR¹ is hydrogen, alkyl of 1 to 4carbon atoms or alkenyl of 2 to 4 carbon atoms; and R² is phenyl;naphthyl or phenyl substituted by:a. 1 or 2 members selected from thegroup consisting of straight or branched-chain alkyl and trifluoromethylmoieties of 1 to 4 carbon atoms; b. alkoxy of 1 to 4 carbon atoms; c.cycloalkyl of 5 or 6 carbon atoms; d. 1 or 2 fluoro, chloro, bromo oriodo moieties; e. chloro or bromo and alkyl of 1 or 2 carbon atoms,trifluoromethyl; or f. nitro.
 26. A method according to claim 21whereinR¹ is hydrogen, methyl or ethyl; X is ethylene, ethylele wherein1 hydrogen atom on one of the carbon atoms is substituted by alkyl of 1or 2 carbons or ethylene wherein 1 hydrogen atom on each of the twocarbon atoms are substituted by alkyl of 1 or 2 carbon atoms, linked toR² via an oxygen or sulphur atom; and R² is phenyl; naphthyl; or phenylsubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl,nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,cyclohexyl, dichlorine, chlorine and methyl, chlorine and bromine,chlorine and fluorine, chlorine and trifluoromethyl, dibromine or methyland trifluoromethyl.
 27. A method according to claim 21 whereinX isethylene, ethylene wherein 1 hydrogen on one of the carbon atoms issubstituted by methyl or ethyl or ethylene wherein 1 hydrogen atom oneach of the two carbon atoms is substituted by methyl, linked to R² viaan oxygen or sulphur atom.
 28. A method according to claim 21 whereinR¹is hydrogen or alkyl or 1 to 4 carbon atoms; X is ethylene or ethylenewherein 1 hydrogen atom on one of the carbon atoms is substituted bymethyl and linked to R² via an oxygen or sulphur atom; and R² is phenyl;naphthyl; or phenyl substituted by 1 or 2 chlorine, methyl, ethyl ortrifluoromethyl moieties.
 29. A method according to claim 21 whereinR¹is hydrogen or alkyl of 1 to 4 carbon atoms; X is ethylene or ethylenewherein 1 hydrogen atom of one of the carbon atoms is substituted bymethyl, linked to R² via an oxygen or sulphur atom; and R² is naphthyl;phenyl; or phenyl substituted by chlorine, methyl, trifluoromethyl,dichlorine, dimethyl, methyl and ethyl or methyl and trifluoromethyl.30. A method according to claim 21 wherein the compound is ##STR60## 31.A method according to claim 21 wherein the compound is ##STR61##
 32. Amethod according to claim 21 wherein the compound is ##STR62##
 33. Amethod according to claim 21 wherein the compound is ##STR63##
 34. Amethod according to claim 21 wherein the compound is ##STR64##
 35. Amethod according to claim 21 wherein the compound is ##STR65##
 36. Amethod according to claim 21 wherein the compound is ##STR66##
 37. Amethod according to claim 21 wherein the compound is ##STR67##
 38. Amethod according to claim 21 wherein the compound is ##STR68##
 39. Amethod according to claim 21 wherein the compound is ##STR69##
 40. Amethod according to claim 21 wherein the compound is ##STR70##